Hyperactive mTORC1/4EBP1 signaling dysregulates proteostasis and accelerates cardiac aging

Area of Science:

• Cardiovascular Biology
• Aging Research
• Molecular Biology

Background:

• Mechanistic target of rapamycin complex 1 (mTORC1) signaling is hyperactivated in aging and age-related diseases.
• mTORC1 regulates proteostasis, a process crucial for cellular health during aging.
• Rapamycin partially inhibiting mTORC1 can reverse age-related cardiac decline in mice.

Purpose of the Study:

• To investigate the role of the mTORC1/4EBP1 signaling axis in age-related cardiac dysfunction.
• To understand the downstream pathways affected by mTORC1/4EBP1 in cardiac aging.

Main Methods:

• Utilized a whole-body 4EBP1 knockout (KO) mouse model to mimic a hyperactive mTORC1/4EBP1/eIF4E axis.
• Performed echocardiography to assess cardiac function (systolic and diastolic) in middle-aged and old 4EBP1 KO and wild-type (WT) mice.
• Analyzed gene expression of heart failure markers, ribosomal biogenesis, and protein ubiquitination in cardiac tissues.

Main Results:

• 4EBP1 KO mice exhibited impaired diastolic function and myocardial performance, indicative of accelerated cardiac aging compared to age-matched WT mice.
• Old 4EBP1 KO mice showed further deterioration in systolic and diastolic function.
• Increased ribosomal biogenesis and protein ubiquitination were observed in 4EBP1 KO hearts, suggesting proteostasis dysregulation.

Conclusions:

• A hyperactive mTORC1/4EBP1 axis accelerates cardiac aging in mice.
• This accelerated cardiac aging may be driven by dysregulation of proteostasis.
• The mTORC1/4EBP1 pathway is a potential therapeutic target for mitigating age-related cardiac dysfunction.